1. Field of the Invention
This invention provides a method for the synthesis of 2-aralkyloxyadenosines and 2-alkoxyadenosines. The invention is particularly useful for the synthesis of 2-[2-(4-chlorophenyl)ethoxy]adenosine.
2. Description of the Related Art
It is generally thought that adenosine has a number of biological functions through its activation of four cell membrane receptors classified as A1, A2A, A2B, and A3. These receptors are believed to elicit their biological activities through typical signal transduction pathways.
Chemical analogs of adenosine can function as either agonists or antagonists and may bind selectively to the individual subclasses of adenosine receptors. For example, it has been demonstrated that selective adenosine A2A receptor agonists, when applied topically, can significantly accelerate wound healing with both normal and impaired healing capacity. In particular, it has been shown that 2-[2-(4-chlorophenyl)ethoxy]adenosine promotes more rapid closure of excisional wounds in normal healthy mice than 0.01% becaplermin gel, an agent currently approved for use in the treatment of diabetic foot ulcers.
The preparation of 2-[2-(4-chlorophenyl)ethoxy]-adenosine and other 2-aralkoxyadenosines and 2-alkoxyadenosines has typically heretofore involved the displacement of the chloro group of 2′,3′-O-(ethoxymethylidene)-2-chloroadenosine or 2′,3′-O-(isopropylidene)-2-chloroadenosine with the appropriate sodium or lithium (Ar)alkoxide followed by de-protection and purification of the desired product. Blocking of the 2′- and 3′-hydroxyl groups is generally considered to be important to prevent the formation of a 2-2′ polymeric product. It has also been indicated that the lability of the glycosidic N-9 C-1′ bond to the acidic conditions required to remove the 2′,3′-blocking group contributes to the low yields observed in the preparation of these selective adenosine A2A agonists.
However, these synthetic routes are lengthy and often produce compounds in low yield, and that are difficult to purify. It would be desirable to have new methods to synthesize 2-aralkyloxyadenosines and 2-alkoxyadenosines. Preferably new synthetic processes would be scalable, would produce the desired compound with a high purity, and not least important, would reduce the cost of producing the desired compound on a large scale. It would be particularly desirable to develop new methods to synthesize 2-[2-(4-chlorophenyl)ethoxy]adenosine.